The present invention relates to substituted 1H-(indole-2-carboxamides and 6H-thieno[2,3-b]pyrrole-5-Carboxamides which are antidiabetic agents and as such are useful in the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, and tissue ischemia, particularly myocardial ischemia.
This invention also relates to a method of using such compounds in the treatment of the above diseases in mammals, especially humans, and to the pharmaceutical compositions useful therefor.
In spite of the early discovery of insulin and its subsequent widespread use in the treatment of diabetes, and the later discovery of and use of sulfonylureas, biguanides and thiazolidinediones, such as troglitazone, rosiglitazone or pioglitazone, as oral hypoglycemic agents, the treatment of diabetes remains less than satisfactory.
The use of insulin requires multiple daily doses, usually by self injection. Determination of the proper dosage of insulin requires frequent estimations of the sugar in urine or blood. The administration of an excess dose of insulin causes hypoglycemia, with effects ranging from mild abnormalities in blood glucose to coma, or even death. Treatment of non-insulin dependent diabetes mellitus (Type II diabetes, NIDDM) usually consists of a combination of diet, exercise, oral hypoglycemic agents, e.g., thiazolidinediones, and in more severe cases, insulin. However, the clinically available hypoglycemic agents can have side effects that limit their use, or an agent may not be effective with a particular patient. In the case of insulin dependent diabetes mellitus (Type I), insulin is usually the primary course of therapy. Hypoglycemic agents that have fewer side effects or succeed where others fail are needed.
Atherosclerosis, a disease of the arteries, is recognized to be the leading cause of death in the United States and Western Europe. The pathological sequence leading to atherosclerosis and occlusive heart disease is well known. The earliest stage in this sequence is the formation of xe2x80x9cfatty streaksxe2x80x9d in the carotid, coronary and cerebral arteries and in the aorta. These lesions are yellow in color due to the presence of lipid deposits found principally within smooth-muscle cells and in macrophages of the intima layer of the arteries and aorta. Further, it is postulated that most of the cholesterol found within the fatty streaks, in turn, give rise to development of the xe2x80x9cfibrous plaque,xe2x80x9d which consists of accumulated intimal smooth muscle cells laden with lipid and surrounded by extra-cellular lipid, collagen, elastin and proteoglycans. The cells plus matrix form a fibrous cap that covers a deeper deposit of cell debris and more extra cellular lipid. The lipid is primarily free and esterified cholesterol. The fibrous plaque forms slowly, and is likely in time to become calcified and necrotic, advancing to the xe2x80x9ccomplicated lesion,xe2x80x9d which accounts for the arterial occlusion and tendency toward mural thrombosis and arterial muscle spasm that characterize advanced atherosclerosis.
Epidemiological evidence has firmly established hyperlipidemia as a primary risk factor in causing cardiovascular disease (CVD) due to atherosclerosis. In recent years, leaders of the medical profession have placed renewed emphasis on lowering plasma cholesterol levels, and low density lipoprotein cholesterol in particular, as an essential step in prevention of CVD. The upper limits of xe2x80x9cnormalxe2x80x9d are now known to be significantly lower than heretofore appreciated. As a result, large segments of Western populations are now realized to be at particularly high risk. Such independent risk factors include glucose intolerance, left ventricular hypertrophy, hypertension, and being of the male sex. Cardiovascular disease is especially prevalent among diabetic subjects, at least in part because of the existence of multiple independent risk factors in this population. Successful treatment of hyperlipidemia in the general population, and in diabetic subjects in particular, is therefore of exceptional medical importance.
Hypertension (or high blood pressure) is a condition which occurs in the human population as a secondary symptom to various other disorders such as renal artery stenosis, pheochromocytoma or endocrine disorders. However, hypertension is also evidenced in many patients in whom the causative agent or disorder is unknown. While such xe2x80x9cessentialxe2x80x9d hypertension is often associated with disorders such as obesity, diabetes and hypertriglyceridemia, the relationship between these disorders has not been elucidated. Additionally, many patients display the symptoms of high blood pressure in the complete absence of any other signs of disease or disorder.
It is known that hypertension can directly lead to heart failure, renal failure and stroke (brain hemorrhaging). These conditions are capable of causing death in a patient. Hypertension can also contribute to the development of atherosclerosis and coronary disease. These conditions gradually weaken a patient and can lead to death.
The exact cause of essential hypertension is unknown, though a number of factors are believed to contribute to the onset of the disease. Among such factors are stress, uncontrolled emotions, unregulated hormone release (the renin, angiotensin, aldosterone system), excessive salt and water due to kidney malfunction, wall thickening and hypertrophy of the vasculature resulting in constricted blood vessels and genetic factors.
The treatment of essential hypertension has been undertaken bearing the foregoing factors in mind. Thus, a broad range of beta-blockers, vasoconstrictors, angiotensin converting enzyme inhibitors and the like have been developed and marketed as antihypertensives. The treatment of hypertension utilizing these compounds has proven beneficial in the prevention of short-interval deaths such as heart failure, renal failure and brain hemorrhaging. However, the development of atherosclerosis or heart disease due to hypertension over a long period of time remains a problem. This implies that although high blood pressure is being reduced, the underlying cause of essential hypertension is not responding to this treatment.
Hypertension has been associated with elevated blood insulin levels, a condition known as hyperinsulinemia. Insulin, a peptide hormone whose primary actions are to promote glucose utilization, protein synthesis and the formation and storage of neutral lipids, also acts to promote vascular cell growth and increase renal sodium retention, among other things. These latter functions can be accomplished without affecting glucose levels and are known causes of hypertension. Peripheral vasculature growth, for example, can cause constriction of peripheral capillaries while sodium retention increases blood volume. Thus, the lowering of insulin levels in hyperinsulinemics can prevent abnormal vascular growth and renal sodium retention caused by high insulin levels and thereby alleviate hypertension.
Cardiac hypertrophy is a significant risk factor in the development of sudden death, myocardial infarction, and congestive heart failure. These cardiac events are due, at least in part, to increased susceptibility to myocardial injury after ischemia and reperfusion that can occur in out-patient as well as perioperative settings. There is an unmet medical need to prevent or minimize adverse myocardial perioperative outcomes, particularly perioperative myocardial infarction. Both non-cardiac and cardiac surgery are associated with substantial risks for myocardial infarction or death. Some 7 million patients undergoing non-cardiac surgery are considered to be at risk, with incidences of perioperative death and serious cardiac complications as high as 20-25% in some series. In addition, of the 400,000 patients undergoing coronary by-pass surgery annually, perioperative myocardial infarction is estimated to occur in 5% and death in 1-2%. There is currently no marketed drug therapy in this area which reduces damage to cardiac tissue from perioperative myocardial ischemia or enhances cardiac resistance to ischemic episodes. Such a therapy is anticipated to be life-saving and reduce hospitalizations, enhance quality of life and reduce overall health care costs of high risk patients. The mechanism(s) responsible for the myocardial injury observed after ischemia and reperfusion is not fully understood. It has been reported (M. F. Allard, et al., Am. J. Physiol., 267: H66-H74 (1994)) that xe2x80x9cpre ischemic glycogen reduction . . . is associated with improved post ischemic left ventricular functional recovery in hypertrophied rat heartsxe2x80x9d.
In addition to myocardial ischemia, other tissues can undergo ischemia and be damaged resulting in serious problems for the patient. Examples of such tissues include cardiac, brain, liver, kidney, lung, gut, skeletal muscle, spleen, pancreas, nerve, spinal cord, retina tissue, the vasculature, or intestinal tissue.
Hepatic glucose production is an important target for NIDDM therapy. The liver is the major regulator of plasma glucose levels in the post absorptive (fasted) state, and the rate of hepatic glucose production in NIDDM patients is significantly elevated relative to normal individuals. Likewise, in the postprandial (fed) state, where the liver has a proportionately smaller role in the total plasma glucose supply, hepatic glucose production is abnormally high in NIDDM patients.
Glycogenolysis is an important target for interruption of hepatic glucose production. The liver produces glucose by glycogenolysis (breakdown of the glucose polymer glycogen) and gluconeogenesis (synthesis of glucose from 2- and 3-carbon precursors). Several lines of evidence indicate that glycogenolysis may make an important contribution to hepatic glucose output in NIDDM. First, in normal post absorptive man, up to 75% of hepatic glucose production is estimated to result from glycogenolysis. Second, patients having liver glycogen storage diseases, including Hers"" disease (glycogen phosphorylase deficiency), display episodic hypoglycemia. These observations suggest that glycogenolysis may be a significant process for hepatic glucose production.
Glycogenolysis is catalyzed in liver, muscle, and brain by tissue-specific isoforms of the enzyme glycogen phosphorylase. This enzyme cleaves the glycogen macromolecule to release glucose-1-phosphate and a new shortened glycogen macromolecule. Several types of glycogen phosphorylase inhibitors have been reported to date: glucose and glucose analogs [Martin, J. L. et al., Biochemistry, 30:10101 (1991)]; caffeine and other purine analogs [Kasvinsky, P. J. et al., J. Biol. Chem., 253: 3343-3351 and 9102-9106 (1978)]; substituted N-(indole-2-carbonyl)-amides [PCT Publication Number WO 96/39385]; and substituted N-(indole-2-carbonyl)-glycinamides [PCT Publication Number WO 96/39384]. These compounds and glycogen phosphorylase inhibitors in general, have been postulated to be of use for the treatment of NIDDM by decreasing hepatic glucose production and lowering glycemia. [Blundell, T. B. et al., Diabetologia, 35: Suppl. 2, 569-576 (1992) and Martin et al., Biochemistry, 30: 10101 (1991)].
Myocardial ischemic injury can occur in outpatient as well as in perioperative settings and can lead to the development of sudden death, myocardial infarction or congestive heart failure. There is an unmet medical need to prevent or minimize myocardial ischemic injury, particularly perioperative myocardial infarction. Such a therapy is anticipated to be life-saving and reduce hospitalizations, enhance quality of life and reduce overall health care costs of high risk patients.
Although there are a variety of hyperglycemia, hypercholesterolemia, hypertension, hyperlipidemia, atherosclerosis and tissue ischemia therapies, there is a continuing need and a continuing search in this field of art for alternative therapies.
The present invention relates to a compound of the formula 
or the pharmaceutically acceptable salt thereof; wherein
n is 0, 1, 2, 3 or 4;
m is 0, 1, 2, 3 or 4;
Z is oxygen or sulfur;
R1 is 
wherein the dashed lines represent optional double bonds;
a is 1, 2 or 3;
each R2 is independently hydrogen, halo, hydroxy, amino, nitro, (C1-C6)alkoxy, cyano, C(O)H or (C1-C6)alkyl optionally substituted by one to three fluoro atoms;
R3 is hydrogen, halo, cyano, (C1-C6)alkyl or (C1-C3)alkynyl;
R4 is hydrogen, halo, cyano or (C1-C6)alkyl;
R5 is 
wherein the dashed lines represent optional double bonds;
A, B and E are each independently nitrogen or CR15;
X and Y are each independently CH2, oxygen, S(O)d wherein d is 0, 1 or 2; nitrogen or NR16;
R8, R9, R10 and R11 are each independently hydrogen or (C1-C6)alkyl;
R12 is hydrogen, HC(O)(C0-C6)alkyl, carboxy(C0-C3)alkyl, R17R18Nxe2x80x94C(O)xe2x80x94(C0-C3)alkyl, hydroxy(C1-C3)alkyl, R17(C1-C3)alkyl, R17R18N(C0-C3)alkyl, (C1-C6)alkyl-C(O)xe2x80x94NH, (C6-C10)aryl-C(O)xe2x80x94NH, (C6-C10)aryl(C1-C6)alkyl-C(O)xe2x80x94NH, (C2-C9)heteroaryl(C1-C6)alkyl-C(O)xe2x80x94NH, (C1-C6)alkylaminocarbonylamino, (C6-C10)arylaminocarbonylamino, (C6-C10)aryl(C1-C6)alkylaminocarbonylamino, (C2-C9)heteroaryl(C1-C6)alkylaminocarbonylamino, (C1-C6)alkylsulfonylamino, (C6-C10)aryl(C1-C6)alkylsulfonylamino, (C2-C9)heteroarylsulfonylamino, (C2-C9)heteroaryl(C1-C6)alkylsulfonylamino, (C1-C6)alkylsulfonyl N((C1-C6)alkyl), (C6-C10)aryl(C1-C6)alkylsulfonyl N((C1-C6)alkyl), (C2-C9)heteroarylsulfonyl N((C1-C6)alkyl), (C2-C9)heteroaryl(C1-C6)alkylsulfonyl N((C1-C6)alkyl), (C3-C7)cycloalkylamino, ((C3-C7)cycloalkyl)2amino, (C3-C7)cycloalkylcarbonylamino, (C6-C10)aryl(C3-C7)cycloalkylcarbonylamino, (C2-C9)heteroaryl(C3-C7)cycloalkylcarbonylamino, (C3-C7)cycloalkylaminocarbonylamino, (C6-C10)aryl(C3-C7)cycloalkylaminocarbonylamino, (C2-C9)heteroaryl(C3-C7)cycloalkylaminocarbonylamino, (C3-C7)cycloalkylsulfonylamino, (C6-C10)aryl(C3-C7)cycloalkylsulfonylamino, (C2-C9)heteroaryl(C3-C7)cycloalkylsulfonylamino, (C3-C7)cycloalkylsulfonyl N((C3-C7)cycloalkyl), (C6-C10)aryl(C3-C7)cycloalkylsulfonyl N((C3-C7)cycloalkyl, (C2-C9)heteroarylsulfonyl N((C3-C7)cycloalkyl), (C2-C9)heteroaryl(C3-C7)cycloalkylsulfonyl N((C3-C7)cycloalkyl), (C1-C6)alkyl S(O)c, (C3-C7)cycloalkyl S(O)c, (C6-C10)aryl(C1-C6)alkyl S(O)c, (C6-C10)aryl S(O)c, (C1-C6)alkylamino S(O)c, (C1-C6)arylamino S(O)c, (C6-C10)arylC1-C6)alkylamino S(O)c wherein c is 0, 1 or 2;
R13 is hydrogen or (C1-C6)alkyl;
R14 is hydrogen, hydroxy, (C1-C6)alkoxy, (C6-C10)aryloxy or NR17R18;
R15 is hydrogen, (C1-C6)alkylcarbonylcarboxy, hydroxy(C1-C6)alkyl, (C1-C6)alkyl piperazinylcarbonyl or piperidinylcarbonyl;
R16 is hydrogen, HCO, (C1-C6)alkyl, (C1-C6)alkoxycarbonyl(C1-C6)alkyl, carboxy(C1-C6)alkyl, piperidinyl(C1-C6)alkylcarbonyl; (C1-C6)acyl; piperidinyl carbonyl(C1-C6)alkyl, hydroxy(C1-C6)alkyl, halo(C1-C6)alkylcarbonyl or morpholinyl(C1-C6)alkylcarbony;
R17 and R18 are each independently hydrogen, (C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkyl and (C2-C9)heteroaryl(C1-C6)alkyl.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
The term xe2x80x9calkoxyxe2x80x9d, as used herein, includes O-alkyl groups wherein xe2x80x9calkylxe2x80x9d is defined above.
The term xe2x80x9carylxe2x80x9d, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl, optionally substituted by 1 to 3 substituents selected from the group consisting of fluoro, chloro, trifluoromethyl, (C1-C6)alkoxy, (C6-C10)aryloxy, trifluoromethoxy, difluoromethoxy and (C1-C6)alkyl.
The term xe2x80x9cheteroarylxe2x80x9d, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic heterocycle by removal of one hydrogen, such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuryl, benzothienyl, indolyl, isoindolyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, thienopyrrolyl or azaindolyl, optionally substituted by 1 to 3 substituents selected from the group consisting of fluoro, chloro, trifluoromethyl, (C1-C6)alkoxy, (C6-C10)aryloxy, trifluoromethoxy, difluoromethoxy and (C1-C6)alkyl.
Preferred compounds of formula I include those wherein R1 is 
wherein a is 1 or 2; and each R2 is independently halo, amino or (C1-C6)alkyl optionally substituted by one to three fluoro atoms.
Preferred compounds of formula I include those wherein n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; and Z is oxygen.
Preferred compounds of formula I include those wherein R5 is 
wherein A, B and E are CR15;
X is oxygen or nitrogen;
Y is oxygen or NR16;
R12 is hydrogen, (C1-C6)alkyl, hydroxy(C1-C6)alkyl or carboxy;
R15 is hydrogen, (C1-C6)alkylcarbonylcarboxy, hydroxy(C1-C6)alkyl, (C1-C6)alkyl piperazinylcarbonyl or piperidinylcarbonyl;
R16 is HCO, (C1-C6)alkyl, (C1-C6)alkoxycarbonyl(C1-C6)alkyl, carboxy(C1-C6)alkyl, piperidinyl(C1-C6)alkylcarbonyl; (C1-C6)acyl; piperidinyl carbonyl(C1-C6)alkyl, hydroxy(C1-C6)alkyl, halo(C1-C6)alkylcarbonyl or morpholinyl(C1-C6)alkylcarbonyl.
Other preferred compounds of formula I include those wherein R5 is 
wherein A is CR15;
B and E are each independently CR15 or nitrogen; and
X and Y are each independently nitrogen or CH2.
Other preferred compounds of formula I include those wherein R5 is 
wherein A is CR15;
B and E are each independently oxygen or nitrogen; and
X and Y are each independently nitrogen or CH2.
Most preferred compounds of formula I include those wherein R1 is 
wherein a is 1 or 2; and each R2 is independently halo, amino or (C1-C6)alkyl optionally substituted by one to three fluoro atoms; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; Z is oxygen and R5 is 
wherein A, B and E are CR15;
X is oxygen or nitrogen;
Y is oxygen or NR16;
R12 is hydrogen, (C1-C6)alkyl, hydroxy(C1-C6)alkyl or carboxy;
R15 is hydrogen, (C1-C6)alkylcarbonylcarboxy, hydroxy(C1-C6)alkyl, (C1-C6)alkyl piperazinylcarbonyl or piperidinylcarbonyl;
R16 is HCO, (C1-C6)alkyl, (C1-C6)alkoxycarbonyl(C1-C6)alkyl, carboxy(C1-C6)alkyl, piperidinyl(C1-C6)alkylcarbonyl; (C1-C6)acyl; piperidinyl carbonyl(C1-C6)alkyl, hydroxy(C1-C6)alkyl, halo(C1-C6)alkylcarbonyl or morpholinyl(C1-C6)alkylcarbonyl.
Most preferred compounds of formula I include those wherein R1 is 
wherein a is 1 or 2; and each R2 is independently halo, amino or (C1-C6)alkyl optionally substituted by one to three fluoro atoms; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; Z is oxygen and R5 is 
wherein A is CR15;
B and E are each independently CR15 or nitrogen; and
X and Y are each independently nitrogen or CH2.
Most preferred compounds of formula I include those wherein R1 is 
wherein a is 1 or 2; and each R2 is independently halo, amino or (C1-C6)alkyl optionally substituted by one to three fluoro atoms; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; Z is oxygen and R5 is 
wherein A is CR15;
B and E are each independently CR15 or nitrogen; and
X and Y are each independently nitrogen or CH2.
Specific preferred compounds of formula I include those wherein said compound is selected from the group consisting of:
5-Chloro-1H-indole-2-carboxylic acid (4-hydroxymethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl)-amide;
5-Chloro-1H-indole-2-carboxylic acid (9-methanesulfonylamino-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;
5-Chloro-1H-indole-2-carboxylic acid (9-hydroxymethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;
{8-[(5-Chloro-1H-indole-2-carbonyl)-amino]-3,4-dihydro-2H-benzo[b][1,4]dioxepin-6-ylamino}-acetic acid ethyl ester;
{2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-4-hydroxymethyl-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl}-acetic acid;
5-Chloro-1H-indole-2-carboxylic acid (9-amino-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;
5-Chloro-1H-indole-2-carboxylic acid [9-(2-hydroxy-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl]-amide;
{2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-7,8-dihydro-6H-5-oxa-9-aza-benzocyclohepten-9-yl}-acetic acid;
5-Methyl-1H-indole-2-carboxylic acid (9-hydroxymethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;
5-Chloro-1H-indole-2-carboxylic acid {9-[2-(3,4-dihydroxy-pyrrolidin-1-yl)-2-oxo-ethyl]-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl}-amide;
5-Chloro-1H-indole-2-carboxylic acid [4-(piperidine-1-carbonyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl]-amide;
5-Chloro-1H-indole-2-carboxylic acid (3,4-dihydro-2H-benzo[1,4]oxazin-6-yl)-amide;
5-Chloro-1H-indole-2-carboxylic acid (3,5-dichloro-4-hydroxy-phenyl)-amide;
5-Fluoro-1H-indole-2-carboxylic acid (6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl)-amide;
5-Chloro-1H-indole-2-carboxylic acid [9-(2-hydroxy-ethylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide;
5-Chloro-1H-indole-2-carboxylic acid (6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl)-amide;
5-Chloro-1H-indole-2-carboxylic acid (9-methyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl)-amide;
2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-4-carboxylic acid;
5-Chloro-1H-indole-2-carboxylic acid (3-hydroxy-4-methoxy-phenyl)-amide;
5-Chloro-1H-indole-2-carboxylic acid (3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;
5-Methyl-1H-indole-2-carboxylic acid (6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl)-amide;
5-Chloro-1H-indole-2-carboxylic acid (9-dimethylcarbamoyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;
5-Chloro-1H-indole-2-carboxylic acid [9-(2-oxo-2-pyrrolidin-1-yl-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl]-amide;
5-Bromo-1H-indole-2-carboxylic acid (3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;
5-Methyl-1H-indole-2-carboxylic acid (2,3,4,5-tetrahydro-benzo[b]dioxocin-8-yl)-amide;
8-[(5-Chloro-1H-indole-2-carbonyl)-amino]-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid;
5-Methyl-1H-indole-2-carboxylic acid (3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;
5-Chloro-1H-indole-2-carboxylic acid [9-(3,4-dihydroxy-pyrrolidine-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide;
5-Chloro-1H-indole-2-carboxylic acid [4-(4-methyl-piperazine-1-carbonyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl]-amide;
1H-Indole-2-carboxylic acid (9-hydroxymethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;
1H-Indole-2-carboxylic acid (3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;
5-Chloro-1H-indole-2-carboxylic acid [9-(4-methyl-piperazine-1-carbonyl)-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl]-amide;
5-Fluoro-1H-indole-2-carboxylic acid (3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-amide;
5-Chloro-1H-indole-2-carboxylic acid {9-[(2-hydroxy-ethylcarbamoyl)-methyl]-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl}-amide;
2-[(5-Chloro-1H-indole-2-carbonyl)-amino]-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene-4-carboxylic acid methyl ester;
5-Chloro-1H-indole-2-carboxylic acid [9-(2-hydroxy-ethyl)-4-hydroxymethyl-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-2-yl]-amide;
1H-Indole-2-carboxylic acid (2,3,4,5-tetrahydro-benzo[b]dioxocin-8-yl)-amide; and
5-Fluoro-1H-indole-2-carboxylic acid (2,3,4,5-tetrahydro-benzo[b]dioxocin-8-yl)-amide.
Also provided are pharmaceutical compositions comprising a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating or preventing atherosclerosis, the methods comprising the step of administering to a patient having atherosclerosis or at risk of having atherosclerosis a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating diabetes, the methods comprising the step of administering to a patient having diabetes a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrug.
In a preferred embodiment of the methods of treating diabetes, the diabetes is non-insulin dependent diabetes mellitus (Type II).
In another preferred embodiment of the methods of treating diabetes, the diabetes is insulin dependent diabetes mellitus (Type I).
Also provided are methods of treating insulin resistance, the methods comprising the step of administering to a patient having insulin resistance a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating diabetic neuropathy, the methods comprising the step of administering to a patient having diabetic neuropathy a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating diabetic nephropathy, the methods comprising the step of administering to a patient having diabetic nephropathy a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating diabetic retinopathy, the methods comprising the step of administering to a patient having diabetic retinopathy a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating cataracts, the methods comprising the step of administering to a patient having cataracts a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating or preventing hypercholesterolemia, the methods comprising the step of administering to a patient having hypercholesterolemia or at risk of having hypercholesterolemia a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating or preventing hypertriglyceridemia, the methods comprising the step of administering to a patient having hypertriglyceridemia or at risk of having hypertriglyceridemia a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating or preventing hyperlipidemia, the methods comprising the step of administering to a patient having hyperlipidemia or at risk of having hyperlipidemia a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating hyperglycemia, the methods comprising the step of administering to a patient having hyperglycemia or at risk of having hyperglycemia therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating hypertension, the methods comprising the step of administering to a patient having hypertension or at risk of having hypertension a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating or preventing tissue ischemia, the methods comprising the step of administering to a patient having tissue ischemia or at risk of having tissue ischemia a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of treating or preventing myocardial ischemia, the methods comprising the step of administering to a patient having myocardial ischemia or at risk of having myocardial ischemia a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are methods of inhibiting glycogen phosphorylase, the methods comprising the step of administering to a patient in need of glycogen phosphorylase inhibition, a glycogen phosphorylase inhibiting amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs.
Also provided are kits for the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, or cataracts in a patient having diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, or cataracts, the kits comprising:
a) a first pharmaceutical composition comprising a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs of the compounds of Formula I, and pharmaceutically acceptable salts of the prodrugs;
b) a second pharmaceutical composition comprising a second compound useful for the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, or cataracts; and
c) a container for containing the first and second compositions.
In a preferred embodiment of the kits, the second compound is selected from:
insulin and insulin analogs;
GLP-1 (7-37) (insulinotropin) and GLP-1 (7-36)-NH2;
sulfonylureas and analogs;
biguanides;
xcex12-antagonists;
imidazolines;
glitazones (thiazolidinediones);
PPAR-gamma agonists;
fatty acid oxidation inhibitors;
xcex1-glucosidase inhibitors;
xcex2-agonists;
phosphodiesterase Inhibitors;
lipid-lowering agents:
antiobesity agents
vanadate, vanadium complexes and peroxovanadium complexes;
amylin antagonists;
glucagon antagonists;
gluconeogenesis inhibitors;
somatostatin analogs and antagonists; and
antilipolytic agents.
In another preferred embodiment of the kits, the second compound is selected from LysPro insulin, GLP-1 (7-37) (insulinotropin), GLP-1 (7-36)-NH2, chlorpropamide, glibenclamide, tolbutamide, tolazamide, acetohexamide, glypizide, glimepiride, repaglinide, meglitinide; mefformin, phenformin, buformin, midaglizole, isaglidole, deriglidole, idazoxan, efaroxan, fluparoxan, linogliride, ciglitazone, pioglitazone, englitazone, troglitazone, darglitazone, rosiglitazone, clomoxir, etomoxir, acarbose, miglitol, emiglitate, voglibose, MDL-25,637, camiglibose, MDL-73,945, BRL 35135, BRL 37344, Ro 16-8714, ICI D7114, CL 316,243, L-386,398; benfluorex, fenfluramine, Naglivan(copyright), acipimox, WAG 994, Symlin(trademark), AC2993 and nateglinide.
In still another preferred embodiment of the kits, the second compound is selected from insulin, sulfonylureas, biguanides, and thiazolidinediones.
Also provided are kits for the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, or tissue ischemia in a patient having diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, or tissue ischemia, the kits comprising:
a) a first pharmaceutical composition comprising a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs of the compounds of Formula I, and pharmaceutically acceptable salts of the prodrugs;
b) a second pharmaceutical composition comprising a second compound useful for the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, or tissue ischemia; and
c) a container for containing the first and second compositions.
Also provided are methods of treating diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, or tissue ischemia, the method comprising the step of administering to a patient having diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, or tissue ischemia, a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs in combination with at least one additional compound useful for the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, or tissue ischemia.
Also provided are pharmaceutical compositions comprising a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of the prodrugs and at least one additional compound useful to treat diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, or tissue ischemia.